It’s clear that glial cells – immune cells found in the brain and the spinal cord – play an important role in producing chronic pain and neuro-inflammation. Glial cell activation in the brain is often measured using the levels of a benzodiazepine receptor, TSPO, which affects immune and neurosteroid functioning in the body and/or brain.
In the brain, TSPO regulates the production of neurosteroids which affect GABA. Low GABA levels are associated with chronic pain, mood disorders, and some neurological diseases.
Depending on TSPO’s activities it can either enhance GABA levels and reduce pain, or reduce GABA levels and increase pain. Which way GABA goes is often determined by the amount of serotonin (5-HT) present in the nerve synapses.
Some call serotonin and GABA – the two “feel-good” chemicals in the brain, the ‘great nervous system stabilizers.”
The translocator protein gene is associated with symptom severity and cerebral pain processing in fibromyalgia Eva Kosek a,b,⇑, Sofia Martinsen a, Björn Gerdle c, Kaisa Mannerkorpi d,e, Monika Löfgren f,Indre Bileviciute-Ljungar f, Peter Fransson a, Martin Schalling g, Martin Ingvar a, Malin Ernberg h, Karin B. Jensen a Brain, Behavior, and Immunity xxx (2016) xxx–xxx
This study examined whether FM patients carry gene variants which make it easier for glial cell activation to occur via the TSPO receptor, or which lower the amount of serotonin present. A positive result would suggest that the brains of people with fibromyalgia are genetically susceptible to producing neuroinflammation and/or reducing GABA levels.
Some studies suggest a strong genetic component exists in FM – https://www.ncbi.nlm.nih.gov/pubmed/26266996. Other studies indicate that the nervous system pathways designed to inhibit pain are underperforming in fibromyalgia, while those designed to enhance pain are going full bore.
Somewhat surprisingly no attempts to directly measure the amount of neuroinflammation present in fibromyalgia have been made. One study which found elevated levels of a cytokine (IL-8 – CXCL1) that co-occurs with TSPO in FM patient’s cerebrospinal fluid suggested that glial cell activation may be occurring.
This Swedish study (n=174 FM patients):
- Determined whether FM patients carrying the gene variants which accelerate glial cell activation or diminish serotonin levels experienced more pain
- Used brain imaging to determine if people with these gene variants had increased glial cell activation. They determined this in an indirect way by measuring the activity of a pain-producing pathway that runs from the prefrontal part of the brain to the parietal cortex.
- Assessed pain sensitivity using a pressure test
- Did a subanalysis to determine the effects of anti-depressants on pain
The fibromyalgia patients exhibited a startling propensity to carry the gene variant (TSPO HAB) associated with rapid glial cell activation. Over half of the group (66) carried that gene while another 40% carried a mixed genetic package. Only about 10% of the FM patients carried the low-affinity form of the gene.
The people carrying the gene variants associated with increased glial cell activation did indeed experience higher levels of pain severity and worse fibromyalgia overall (FIQ -fibromyalgia impact quotient). Neither anxiety or depression was affected by the presence of the variant.
Serotonin gene variants, on the other hand, were not themselves associated with increased pain. People carrying both the glial cell activation and the reduced serotonin genetic variants, however, were in the worst shape of all.
The brain imaging results indicated that the 50% or so of the fibromyalgia patients carrying the high glial cell activating variant demonstrated increased activation of a brain network (frontoparietal) believed to play a significant role in increasing “vigilance” and anticipation. If you have difficulty relaxing, if you feel that your system is always on edge, if you have difficulty concentrating or feel “wired and tired” this activated network could be playing a role in that.
These same patients, interestingly enough, did not exhibit increased pain sensitivity. They were in more pain, but they were not more sensitive to painful stimuli. A pressure pain sensitivity test which involved pressing down on a part of the body until pain registered did not, oddly enough, find increased pain sensitivity in this group.
That suggested that the glial cell activation seen in FM may primarily affect hypervigilance and anticipation (even though it did not affect anxiety). Hypervigilance or increased pain anticipation may then play a significant role in the increased pain levels experienced by these patients.
This study suggests that this hypervigilant state may be genetically encoded – ready to pop out when the levels of GABA/ serotonin are reduced, or brain processes are affected by chronic pain. Many studies have shown that vigilance and the anticipation of pain can significantly increase one’s pain levels.
The authors suggested that treatments targeting glial cell activation could be very helpful in fibromyalgia. Jarred Younger is currently testing glial cell inhibitors in both fibromyalgia and gulf war syndrome.
The study results also suggested that FM patients carrying the gene variant that increases the likelihood of glial cell activation might be more likely to benefit from serotonin-enhancing drugs such as SSRIs or SNRIs. A subanalysis found that FM patients with the glial cell enhancing gene variant taking antidepressants were in no more pain than the FM patients with the glial cell activity gene variant; they helped in this set of patients.
The authors did not mention 5-HTP, a serotonin supplement that a 1990 study found helpful. Dr. Murphree asserts that taking 5-HTP is more effective than trying to squeeze out more serotonin from an already depleted system. He’s found 5-HTP to be particularly helpful with sleep. Another natural health practitioner recommends trying passion flower and St. John’s Wort (but not if you’re currently taking antidepressants) to increase GABA/serotonin levels. Another recommends adding magnesium to the mix.
*Also be careful about taking 5-HTP if you’re taking tramadol, dextromethorphan (found in cough syrup) or triptans, as it may increase serotonin too much, resulting in a dangerous condition called serotonin syndrome.
- See Dr. Murphree’s 5-HTP Protocol for Enhancing Sleep in Fibromyalgia
- Using 5-HTP to Increase Serotonin Levels in Fibromyalgia and ME/CFS – From Dr. Murphree
The study suggests that a genetic test could help determine which FM patients would respond to antidepressants. (It should be noted that antidepressants are more than mood enhancers; some “antidepressants” can reduce pain in FM patients who are not depressed.)
Although the authors did not mention them, behavioral approaches designed to reduce hypervigilance and anticipation and induce calm might be helpful as well. Meditation, for instance, has been shown to increase serotonin levels in the brain.
Female fibromyalgia patients carrying a gene variant associated with increased glial cell activation tend to be in more pain and have a lower quality of life than without that gene variant. More studies are needed, but this study suggested that a high proportion (@50%) of FM patients may carry this variant.
A gene variant which reduces serotonin levels by itself does not appear to increase pain but having both gene variants only adds to the problem.
If you have these variants serotonin-enhancing drugs such as SSRIs or SNRI’s (or supplements such as 5-HTP) or behavioral practices such as meditation might be helpful.
FM patients carrying the glial cell enhancing gene variant were in more pain but did not display increased pain sensitivity during a pressure test. This and the finding that the brain pathways affected by this gene variant are associated with hypervigilance suggest that glial cell activation may put some FM patients into a hypervigilant or “wired and tired” state. Many studies indicate that hypervigilance and the anticipation of pain result in increased pain.
Future drugs that target glial cell activation could be helpful in fibromyalgia.